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NCCIH Clinical Trial Funding Opportunity Announcements

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The National Center for Complementary and Integrative Health (NCCIH) no longer accepts most clinical trial applications through the Parent R01 (See NOT-AT-19-011). NCCIH has published a series of clinical trial-specific Funding Opportunity Announcements (FOAs) for investigators to use instead of the Parent R01. They focus on 1) mind and body intervention studies and 2) natural product studies, targeting support of all phases of clinical intervention development.

Clinical trials are particularly important to NCCIH. We study health interventions widely used by the American public—interventions often used with scarce evidence of efficacy. We see substantial promise in many of these interventions, but we recognize that the evidence supporting their use is often incomplete. Our clinical trial FOAs will help to address gaps in current research and build a strong evidence base.

NCCIH Clinical Trial FOAs Support Continuum of Clinical Research

With the continuum of available NCCIH clinical trial FOAs, we support investigators working on the “building blocks” that bridge the gap from basic research to high-impact clinical trials. We provide pathways via these FOAs to support all developmental steps that may lead to major clinical trials on complementary and integrative health approaches. Applications to nearly all of the NCCIH clinical trial FOAs listed below will be assessed by special emphasis review panels familiar with our research priorities and the goals of each FOA.

The National Institutes of Health (NIH) defines a clinical trial as “A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.” (NOT-OD-15-015). NIH defines a mechanistic study (which can be a type of clinical trial) as: “A mechanistic study is designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention.”

NCCIH recognizes a difference between clinical trials that are designed to answer specific questions about the clinical effect of interventions and mechanistic studies that have the primary goal of understanding how an intervention works.

A mechanistic study is defined as one designed to understand the mechanism of action of an intervention, a biological process, or the pathophysiology of a disease.

A clinical outcome study is defined as one with the objective of determining the clinical safety, tolerability, feasibility, efficacy, and/or effectiveness of pharmacologic, nonpharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions.

NCCIH has developed a range of FOAs to support mechanistic research and research on clinical outcomes that support the full spectrum of human subjects research.

How NCCIH Uses the Parent R01 for Human Subjects Research

Parent R01 Clinical Trial Not Allowed (PA-19-056): NCCIH will continue to accept applications to this FOA for observational studies such as survey studies, cohort studies, or case-control studies, as well as secondary analyses of existing data sets or banked samples.

Parent R01 Clinical Trial Required (PA-19-055): NCCIH will only accept applications that propose human mechanistic trials/studies; no applications will be accepted that include any specific aims that propose to assess efficacy or effectiveness of any intervention (see NOT-AT-19-011).

NCCIH has developed a suite of clinical trial FOAs to support the full range of clinical trial types for both mind and body and natural product interventions. Investigators are strongly encouraged to apply to one of NCCIH’s clinical trial FOAs (see Tables below) instead of the Parent R01 FOAs. Applicants are encouraged to contact nccihderinquiries@mail.nih.gov for initial advice on choosing an FOA to match their stage of science. Once applicants have chosen a specific FOA and developed a specific aims page, they are encouraged to contact the Scientific Research contact listed in the FOA and in the table below for further feedback prior to applying.

This Funding Opportunity Announcement (FOA) encourages applications for investigator-initiated multi-site clinical trials (e.g. efficacy, effectiveness or pragmatic trials) to study the effects of mind and body interventions in NCCIH designated areas of high research priority. Clinical Coordinating Centers should develop and implement the proposed multi-site clinical trial. The objective of a Clinical Coordinating Center application is to present the scientific rationale and a comprehensive scientific and operational plan for the clinical trial. Clinical Coordinating Center applications are expected to describe plans for project management, participant recruitment and retention strategies, performance milestones , scientific conduct, and dissemination of results. Clinical Coordinating Center applications submitted under this FOA will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) funding mechanism.

In addition, an accompanying Data Coordinating Center application, submitted under PAR-18-663 proposing a data analysis and data management plan for the clinical project is required. Both a Clinical Coordinating Center application and a corresponding Data Coordinating Center (DCC) application must be submitted simultaneously for consideration by NCCIH.

This Funding Opportunity Announcement (FOA), utilizing the U24 grant funding mechanism, encourages applications for a collaborating Data Coordinating Center (DCC) application that accompanies an investigator-initiated multi-site clinical trial (Phase Ill and beyond) application submitted under PAR-18-662.The DCC application must be specific to the collaborating Clinical Coordinating Center (CCC) application. The objective of the DCC application is to propose a comprehensive plan that provides overall project coordination, and administrative, data management, and biostatistical support for the proposed clinical trial. Both a DCC application and a corresponding CCC application need to be submitted simultaneously for consideration by NCCIH.

The goal of this funding opportunity announcement (FOA) is to support early phase clinical trials of mind and body approaches for conditions that have been identified by NCCIH as high priority research topics. This funding opportunity is intended to support exploratory clinical trials, which will provide data that are critical for the planning and design of a subsequent controlled cohort study, clinical efficacy or effectiveness study, or a pragmatic trial. The data collected should be used to fill gaps in scientific knowledge necessary to develop a competitive full-scale clinical trial. This FOA is not appropriate for support of randomized clinical trials to test or determine efficacy or effectiveness. Applications that propose solely to write a protocol or manual of operations or to develop infrastructure for a clinical trial are not appropriate for this announcement.

Understanding the mechanisms by which complementary or integrative Mind and Body Interventions exert their clinical effects is critical for the development of optimized interventions that target specific conditions and disorders. Building on prior mechanistic research, the purpose of this FOA is to encourage additional research to optimize the biological, neurological, physiological mechanisms or behavioral processes underlying mind and body Interventions.

This Funding Opportunity Announcement (FOA) invites cooperative agreement applications for investigator-initiated clinical trials of mind and body interventions in NCCIH-designated areas of high research priority. Applications submitted under this FOA are expected to propose a clinical trial to develop and test adaptive interventions; optimize the intervention by evaluating which element of a complex intervention are critical for changes in outcome; assessing whether the intervention can be delivered with fidelity across sites in preparation for a future multi-site trial; or collect additional preliminary data such as determining the duration or frequency of the intervention to be used in a future multi-site trial. It is important, therefore, to already have sufficient preliminary data that includes: demonstration of feasibility of recruitment and accrual of participants; demonstration of participant adherence to the intervention as well as retention of participants throughout the study; completion of final data collection from any related studies; and evidence that the intervention has promise of clinical benefit. This FOA is not intended to support multi-site efficacy or effectiveness trials, nor will it support trials to test mind and body interventions for the treatment or prevention of cancer.

Understanding the mechanisms by which complementary or integrative Mind and Body Interventions exert their clinical effects is critical for the development of optimized interventions that target specific conditions and disorders. The purpose of this FOA is to establish a two-phased milestone-driven research approach to investigate and optimize the mechanisms underlying mind and body Interventions. The first R61 phase will investigate the biological, neurological, physiological, and/or mechanisms or behavioral processes underlying a mind and body Intervention. The second R33 phase, may be used to (1) optimize the mechanisms or processes identified in the R61 phase through further modifications to the intervention, (2) study the integration of approaches that may affect the same underlying mechanisms or processes, or (3) further study the relationship between the intervention and the underlying mechanism of action with a relevant target population.

This FOA encourages applications for investigator-initiated early phase clinical trials of natural products (i.e., botanicals, dietary supplements, and probiotics), which have a strong scientific premise to justify further clinical testing. Under this FOA, trials must be designed so that results, whether positive or negative, will provide information of high scientific utility and will support decisions about further development or testing of the natural product.This FOA will provide up to 3 years support for studies to replicate the impact of the natural product on the biological signature(s) when used by humans and assess whether there is an association between the degree of the impact on the biological signature and functional or clinical outcomes in a patient population. Applications can design studies to determine how to optimize the impact of the natural product on the biological signature by (1) optimizing the delivery of the natural product by dose or formulation; (2) combine the natural product with another treatment approach that is known to impact the same biological signature; or (3) study the impact of the natural product in a target population that is more responsive. This FOA will not support efficacy or effectiveness trials, nor will it support trials to test natural products for the treatment or prevention of cancer.

This FOA encourages applications for investigator-initiated early phase clinical trials of natural products (i.e., botanicals, dietary supplements, and probiotics), which have a strong scientific premise to justify further clinical testing. Under this FOA, trials must be designed so that results, whether positive or negative, will provide information of high scientific utility and will support decisions about further development or testing of the natural product.This FOA will provide up to two years (R61 phase) of support for milestone-driven testing of bioavailability, pharmacokinetics, and assessment of the natural products effect (i.e., measure of mechanism of action) when used by humans on a biological signature(s). If milestones in the R61 phase are achieved, up to 3 years of additional support (R33 phase) may be awarded to replicate the impact of the natural product on the biological signature(s) when used by humans and assess whether there is an association between the degree of the impact on the biological signature and functional or clinical outcomes in a patient population. Applications can design R33 studies to determine how to optimize the impact of the natural product on the biological signature by (1) optimizing the delivery of the natural product by dose or formulation; (2) combine the natural product with another treatment approach that is known to impact the same biological signature; or (3) study the impact of the natural product in a target population that is more responsive. This FOA will not support efficacy or effectiveness trials, nor will it support trials to test natural products for the treatment or prevention of cancer.

This FOA encourages cooperative agreement applications for investigator-initiated multi-site clinical trials (Phase III and beyond) to study the effects of natural products in NCCIH designated areas of high research priority. Applicants should describe plans for a Clinical Coordinating Center to develop and implement the proposed multi-site clinical trial. The objective of the Clinical Coordinating Center is to provide the design scientific rationale and a comprehensive scientific and operational plan for the clinical trial. The Clinical Coordinating Center is expected to be responsible for project management, participant recruitment and retention strategies, performance milestones, scientific conduct, and dissemination of results. Clinical Coordinating Center applications submitted under this FOA will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) funding mechanism.

In addition, an accompanying Data Coordinating Center application, submitted under PAR-18-697, proposing a data analysis and data management plan for the clinical project is required.

Both a Clinical Coordinating Center application and a corresponding Data Coordinating Center (DCC) application must be submitted simultaneously for consideration by NCCIH.

This FOA encourages applications for a collaborating Data Coordinating Center (DCC) application that accompanies investigator-initiated, multi-site clinical trials (Phase III and beyond) applications submitted under PAR-18-696. The DCC application must be specific to the collaborating Clinical Coordinating Center (CCC) application. The objective of the DCC application is to propose a comprehensive plan that provides overall project coordination and administrative, data management and biostatistical support for the proposed clinical trial. Both a DCC application and a corresponding CCC application must be submitted simultaneously for consideration by NCCIH.

This Funding Opportunity Announcement (FOA) invites cooperative agreement applications for investigator-initiated clinical trials of natural products to treat clinical symptoms such as those associated with sleep disturbance, pain conditions, or some mental health conditions (e.g., mild to moderate depression, anxiety, and post-traumatic stress), or examine the effects of probiotics and other natural products on gut-microbiome interactions with the brain and/or immune system. All applications submitted under this FOA must be supported by sufficient preliminary data of bioavailability and documentation that the natural product produces a replicable and measurable biological signature (i.e., measure of the mechanism of action), whenever it is possible or practical to measure and used by the patient population of interest.